Impaired Brain Satiety Responses After Weight Loss in Children With Obesity.

CONTEXT: Obesity interventions often result in increased motivation to eat. OBJECTIVE: We investigated relationships between obesity outcomes and changes in brain activation by visual food cues and hormone levels in response to obesity intervention by family-based behavioral treatment (FBT). METHODS: Neuroimaging and hormone assessments were conducted before and after 24-week FBT intervention in children with obesity (OB, n = 28), or children of healthy weight without intervention (HW, n = 17), all 9- to 11-year-old boys and girls. We evaluated meal-induced changes in neural activation to high- vs low-calorie food cues across appetite-processing brain regions and gut hormones. RESULTS: Among children with OB who underwent FBT, greater declines of BMI z-score were associated with lesser reductions after the FBT intervention in meal-induced changes in neural activation to high- vs low-calorie food cues across appetite-processing brain regions (P < 0.05), and the slope of relationship was significantly different compared with children of HW. In children with OB, less reduction in brain responses to a meal from before to after FBT was associated with greater meal-induced reduction in ghrelin and increased meal-induced stimulation in peptide YY and glucagon-like peptide-1 (all P < 0.05). CONCLUSION: In response to FBT, adaptations of central satiety responses and peripheral satiety-regulating hormones were noted. After weight loss, changes of peripheral hormone secretion support weight loss, but there was a weaker central satiety response. The findings suggest that even when peripheral satiety responses by gut hormones are intact, the central regulation of satiety is disturbed in children with OB who significantly improve their weight status during FBT, which could favor future weight regain.

Evidence That Hypothalamic Gliosis Is Related to Impaired Glucose Homeostasis in Adults With Obesity.

OBJECTIVE: Preclinical research implicates hypothalamic glial cell responses in the pathogenesis of obesity and type 2 diabetes (T2D). In the current study we sought to translate such findings to humans by testing whether radiologic markers of gliosis in the mediobasal hypothalamus (MBH) were greater in individuals with obesity and impaired glucose homeostasis or T2D. RESEARCH DESIGN AND METHODS: Using cross-sectional and prospective cohort study designs, we applied a validated quantitative MRI approach to assess gliosis in 67 adults with obesity and normal glucose tolerance, impaired glucose tolerance (IGT), or T2D. Assessments of glucose homeostasis were conducted via oral glucose tolerance tests (OGTT) and ß-cell modeling. RESULTS: We found significantly greater T2 relaxation times (a marker of gliosis by MRI), that were independent of adiposity, in the groups with IGT and T2D as compared with the group with normal glucose tolerance. Findings were present in the MBH, but not control regions. Moreover, positive linear associations were present in the MBH but not control regions between T2 relaxation time and glucose area under the curve during an OGTT, fasting glucose concentrations, hemoglobin A1c, and visceral adipose tissue mass, whereas negative linear relationships were present in the MBH for markers of insulin sensitivity and ß-cell function. In a prospective cohort study, greater MBH T2 relaxation times predicted declining insulin sensitivity over 1 year. CONCLUSIONS: Findings support a role for hypothalamic gliosis in the progression of insulin resistance in obesity and thus T2D pathogenesis in humans.

General and Food-Specific Impulsivity and Inhibition Related to Weight Management.

Background: Understanding child characteristics that relate to weight management treatment outcome could help identify opportunities for intervention innovation or tailoring. The limited evidence available is inconsistent regarding whether and which aspects of children's general or food-specific impulsivity and inhibition relate to treatment outcomes. Methods: Children with (n = 54) and without obesity (n = 22) were compared on various measures of impulsivity and inhibition. Children with obesity (n = 40) then completed family-based treatment for weight management. Analyses examined associations between baseline children's impulsivity and inhibition and child weight status change (BMI z-score) and between treatment-based changes in impulsivity and inhibition and weight status change, with and without adjustment by baseline functional magnetic resonance imaging-measured appetitive drive. Results: Children with obesity scored more poorly on some, but not all, measures of impulsivity and inhibition than children without obesity. Lower baseline general inhibition and greater parent-report of child impulsivity were associated (independently) with greater improvements in child weight status, with modest attenuation after appetite drive adjustment. Children improved task-based general inhibition during treatment. Improvements in general inhibition and snack food discounting were associated with better child weight outcomes, although adjusting for baseline values attenuated these associations. Conclusions: Children with obesity having greater initial impulsivity had better weight outcomes in treatment even after adjusting for initial appetitive drive. In contrast, improvements in task-based inhibition and food-related discounting during treatment were also related to better outcomes. Research is needed on innovative approaches to better address impulsivity and inhibition in children's weight management. Clinical Trial Registration number: NCT02484976.

Reassessing relationships between appetite and adiposity in people at risk of obesity: A twin study using fMRI.

BACKGROUND: Neuroimaging studies suggest that appetitive drive is enhanced in obesity. OBJECTIVE: To test if appetitive drive varies in direct proportion to the level of body adiposity after accounting for genetic factors that contribute to both brain response and obesity risk. SUBJECTS/METHODS: Participants were adult monozygotic (n = 54) and dizygotic (n = 30) twins with at least one member of the pair with obesity. Body composition was assessed by dual-energy X-ray absorptiometry. Hormonal and appetite measures were obtained in response to a standardized meal that provided 20% of estimated daily caloric needs and to an ad libitum buffet meal. Pre- and post-meal functional magnetic resonance imaging (fMRI) assessed brain response to visual food cues in a set of a priori appetite-regulating regions. Exploratory voxelwise analyses outside a priori regions were performed with correction for multiple comparisons. RESULTS: In a group of 84 adults, the majority with obesity (75%), body fat mass was not associated with hormonal responses to a meal (glucose, insulin, glucagon-like peptide-1 and ghrelin, all P>0.40), subjective feelings of hunger (ß=-0.01 mm [95% CI -0.35, 0.34] P = 0.97) and fullness (ß=0.15 mm [-0.15, 0.44] P = 0.33), or buffet meal intake in relation to estimated daily caloric needs (ß=0.28% [-0.05, 0.60] P = 0.10). Body fat mass was also not associated with brain response to high-calorie food cues in appetite-regulating regions (Pre-meal ß=-0.12 [-0.32, 0.09] P = 0.26; Post-meal ß=0.18 [-0.02, 0.37] P = 0.09; Change by a meal ß=0.29 [-0.02, 0.61] P = 0.07). Conversely, lower fat mass was associated with being weight reduced (ß=-0.05% [-0.07, -0.03] P<0.001) and greater pre-meal activation to high-calorie food cues in the dorsolateral prefrontal cortex (Z = 3.63 P = 0.017). CONCLUSIONS: In a large study of adult twins, the majority with overweight or obesity, the level of adiposity was not associated with excess appetitive drive as assessed by behavioral, hormonal, or fMRI measures.

Child neurobiology impacts success in family-based behavioral treatment for children with obesity.

BACKGROUND AND OBJECTIVES: Family-based behavioral treatment (FBT) is the recommended treatment for children with common obesity. However, there is a large variability in short- and long-term treatment response, and mechanisms for unsuccessful treatment outcomes are not fully understood. In this study, we tested if brain response to visual food cues among children with obesity before treatment predicted weight or behavioral outcomes during a 6-month behavioral weight management program and/or long-term relative weight maintenance over a 1-year follow-up period. SUBJECTS AND METHODS: Thirty-seven children with obesity (age 9-11 years, 62% male) who entered active FBT (attended two or more sessions) and had outcome data. Brain activation was assessed at pretreatment by functional magnetic resonance imaging across an a priori set of appetite-processing brain regions that included the ventral and dorsal striatum, mOFC, amygdala, substantia nigra/ventral tegmental area, and insula in response to viewing food images before and after a standardized meal. RESULTS: Children with more robust reductions in brain activation to high-calorie food cue images following a meal had greater declines in BMI z-score during FBT (r = 0.42; 95% CI: 0.09, 0.66; P = 0.02) and greater improvements in Healthy Eating Index scores (r = -0.41; 95% CI: -0.67, -0.06; P = 0.02). In whole-brain analyses, greater activation in the ventromedial prefrontal cortex, specifically by high-calorie food cues, was predictive of better treatment outcomes (whole-brain cluster corrected P = 0.02). There were no significant predictors of relative weight maintenance, and initial behavioral or hormonal measures did not predict FBT outcomes. CONCLUSIONS: Children's brain responses to a meal prior to obesity treatment were related to treatment-based weight outcomes, suggesting that neurophysiologic factors and appetitive drive, more so than initial hormone status or behavioral characteristics, limit intervention success.

Salience network connectivity is reduced by a meal and influenced by genetic background and hypothalamic gliosis.

BACKGROUND/OBJECTIVES: The salience network (SN) comprises brain regions that evaluate cues in the external environment in light of internal signals. We examined the SN response to meal intake and potential genetic and acquired influences on SN function. SUBJECTS/METHODS: Monozygotic (MZ; 40 pairs) and dizygotic (15 pairs) twins had body composition and plasma metabolic profile evaluated (glucose, insulin, leptin, ghrelin, and GLP-1). Twins underwent resting-state functional magnetic resonance imaging (fMRI) scans before and after a standardized meal. The strength of SN connectivity was analyzed pre- and post-meal and the percentage change elicited by a meal was calculated. A multi-echo T2 MRI scan measured T2 relaxation time, a radiologic index of gliosis, in the mediobasal hypothalamus (MBH) and control regions. Statistical approaches included intraclass correlations (ICC) to investigate genetic influences and within-pair analyses to exclude genetic confounders. RESULTS: SN connectivity was reduced by a meal ingestion (ß = -0.20; P < 0.001). Inherited influences on both pre- and post-meal connectivity were present (ICC MZ twins 26%, P < 0.05 and 47%, P < 0.001, respectively), but not percentage change in response to the meal. SN connectivity in response to a meal did not differ between participants with obesity and of normal weight (χ2(1) = 0.93; P = 0.33). However, when participants were classified as having high or low signs of MBH gliosis, the high MBH gliosis group failed to reduce the connectivity in response to a meal (z = -1.32; P = 0.19). Excluding genetic confounders, the percentage change in SN connectivity by a meal correlated to body fat percentage (r = 0.24; P < 0.01). CONCLUSIONS: SN connectivity was reduced by a meal, indicating potential participation of the SN in control of feeding. The strength of SN connectivity is inherited, but the degree to which SN connectivity is reduced by eating appears to be influenced by adiposity and the presence of hypothalamic gliosis.

Central Nervous System and Peripheral Hormone Responses to a Meal in Children.

CONTEXT: Behavioral studies suggest that responses to food consumption are altered in children with obesity (OB). OBJECTIVE: To test central nervous system and peripheral hormone response by functional MRI and satiety-regulating hormone levels before and after a meal. DESIGN AND SETTING: Cross-sectional study comparing children with OB and children of healthy weight (HW) recruited from across the Puget Sound region of Washington. PARTICIPANTS: Children (9 to 11 years old; OB, n = 54; HW, n = 22), matched for age and sex. INTERVENTION AND OUTCOME MEASURES: Neural activation to images of high- and low-calorie food and objects was evaluated across a set of a priori appetite-processing regions that included the ventral and dorsal striatum, amygdala, substantia nigra/ventral tegmental area, insula, and medial orbitofrontal cortex. Premeal and postmeal hormones (insulin, peptide YY, glucagon-like peptide-1, active ghrelin) were measured. RESULTS: In response to a meal, average brain activation by high-calorie food cues vs objects in a priori regions was reduced after meals in children of HW (Z = -3.5, P < 0.0001), but not in children with OB (z = 0.28, P = 0.78) despite appropriate meal responses by gut hormones. Although premeal average brain activation by high-calorie food cues was lower in children with OB vs children of HW, postmeal activation was higher in children with OB (Z = -2.1, P = 0.04 and Z = 2.3, P = 0.02, respectively). An attenuated central response to a meal was associated with greater degree of insulin resistance. CONCLUSIONS: Our data suggest that children with OB exhibit an attenuated central, as opposed to gut hormone, response to a meal, which may predispose them to overconsumption of food or difficulty with weight loss.

FTO genotype impacts food intake and corticolimbic activation.

Background: Variants in the first intron of the fat mass and obesity-associated (FTO) gene increase obesity risk. People with "high-risk" FTO genotypes exhibit preference for high-fat foods, reduced satiety responsiveness, and greater food intake consistent with impaired satiety. Objective: We sought central nervous system mechanisms that might underlie impaired satiety perception in people with a higher risk of obesity based on their FTO genotype. Design: We performed a cross-sectional study in a sample that was enriched for obesity and included 20 higher-risk participants with the AA (risk) genotype at the rs9939609 locus of FTO and 94 lower-risk participants with either the AT or TT genotype. We compared subjective appetite, appetite-regulating hormones, caloric intake at a buffet meal, and brain response to visual food cues in an extended satiety network using functional MRI scans acquired before and after a standardized meal. Results: Higher-risk participants reported less subjective fullness (χ2 = 7.48, P < 0.01), rated calorie-dense food as more appealing (χ2 = 3.92, P < 0.05), and consumed ∼350 more kilocalories than lower-risk participants (ß = 348 kcal, P = 0.03), even after adjusting for fat or lean mass. Premeal, the higher-risk group had greater activation by "fattening" food images (compared with objects) in the medial orbital frontal cortex (ß = 11.6; 95% CI: 1.5, 21.7; P < 0.05). Postmeal, the higher-risk subjects had greater activation by fattening (compared with nonfattening) food cues in the ventral tegmental area/substantia nigra (ß = 12.8; 95% CI: 2.7, 23.0; P < 0.05), amygdala (ß = 10.6; 95% CI: 0.7, 20.5; P < 0.05), and ventral striatum (ß = 6.9; 95% CI: 0.2, 13.7; P < 0.05). Moreover, postmeal activation by fattening food cues within the preselected extended satiety network was positively associated with energy intake at the buffet meal (R2 = 0.29, P = 0.04) and this relation was particularly strong in the dorsal striatum (R2 = 0.28, P = 0.01), amygdala (R2 = 0.28, P = 0.03), and ventral tegmental area/substantia nigra (R2 = 0.27, P = 0.01). Conclusion: The findings are consistent with a model in which allelic variants in FTO raise obesity risk through impaired central nervous system satiety processing, thereby increasing food intake. This study is registered at clinicaltrials.gov as NCT02483663.